tbuckley/cabot-search huggingface dataset:
Abstract 4266: Genomic landscape of prostate cancer: Bioinformatic analysis of TCGA PanCancer data by race and identification of key pathways and genes in PTEN mutation
Authors: Olumide Arigbede, Sarah G. Buxbaum, Sara Falzarano, Suhn K. Rhie
Journal: Cancer Research (2023)

Abstract Issue: Prostate cancer (Pca) is still among the most frequently diagnosed cancers in adults. The most often mutated gene in PCa is PTEN (Phosphatase and Tensin Homolog), making it a possible biomarker for prospective customized therapy. The root causes of health inequalities in PCa have not received much attention. Numerous online databases, like The Cancer Genome Atlas (TCGA), provide gene expression data and other data, allowing researchers to further investigate new processes or therapy options. However, there hasn't been much study on tailored therapy up to this point since there may have been difficulties with access to genomic information and bioinformatic tools. Methods: The PCa data in cBioPortal comprises 494 samples. We selected 154 samples comprising 7 Blacks and 147 Whites. We used the TCGA database to obtain the PCa gene expression and DNA methylation data for study. In order to examine the data by race/ethnicity, gene expression, DNA methylation, and genomic changes, we evaluated at the differentially expressed and methylated genes using online tools (cBioPortal). To evaluate gene methylation, expression, and alterations, log ratios of means in Blacks to means in Whites were computed across the data. Additionally, Kaplan-Meier survival analysis, protein interaction analysis, and multivariable data analysis were carried out. Results: PCa data in the TCGA database showed PTEN mutation in 20% patients. The median age of participants was 63 years (range: 42-78). For every category of data assessed, there were significant differences by race/ethnicity (q &amp;lt; 0.05). In the survival analysis, SLC2A1, NUDT12, CUTALP, and other genes were associated with survival. Conclusion: Genetic alteration, expression, and DNA methylation are each significantly different by the two race groups compared. According to our research, PTEN mutation in PCa may influence several genes and biological processes. Citation Format: Olumide Arigbede, Sarah G. Buxbaum, Sara Falzarano, Suhn K. Rhie. Genomic landscape of prostate cancer: Bioinformatic analysis of TCGA PanCancer data by race and identification of key pathways and genes in PTEN mutation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4266.
Abstract 2440: HOTAIR functionality and regulation in ovarian cancer stem cells
Authors: Weini Wang, Yanchi Zhou, Ji Wang, Ali Ozes, Heather M. O’Hagan, Anirban Mitra, Kenneth P. Nephew
Journal: Cancer Research (2023)

Abstract Ovarian cancer (OC) is the fifth leading cause of cancer-related death among American women. Persistence of OC stem cells (OCSCs) is believed to contribute to resistance to platinum-based chemotherapy and disease relapse. We have previously shown that epigenetic changes in OCSCs play a role in post-therapy OCSC persistence and demonstrated the potential to target OCSC using epigenetic therapies. HOXC transcript antisense RNA (HOTAIR) has been shown to be associated with chemoresistance and overexpressed in high-grade serous OC (HGSOC). HOTAIR interacts with Polycomb Repressive Complex 2 (PRC2) and plays a key role in chromatin remodeling. Because HOTAIR is a known epigenetic regulator of differentiation and developmental genes in OC, we hypothesized that HOTAIR regulates OCSCs and epigenetic targeting HOTAIR will prevent tumor relapse. To produce loss-of-function phenotypes of HOTAIR and investigate the function of this gene, we utilized the paired CRISPR guide RNA design to delete the functional sites of HOTAIR in a panel high grade serous OC cell lines (Kuramochi, OVCAR3) without affecting nearby protein-coding gene. Knockout of HOTAIR re-sensitized OC cells to platinum treatment and significantly decreased (P&amp;lt;0.001) the OCSC population and stemness-related phenotypes, including inhibiting stemness-associated gene expression ALDH1A1, Notch3, Sox9, and PROM1 and in vitro spheroid forming ability under low attachment conditions. Integrated analysis of RNA-seq and ATAC-seq on control and HOTAIR knockout cells revealed HOTAIR altered global chromatin dynamics to change downstream gene expression, particularly, the NF-kB pathway. In xenograft assays using HGSOC cells, combining a HOTAIR inhibitor with an EZH2 inhibitor and chemotherapy significantly decreased in vivo tumor formation and increased mouse survival. In summary, depletion of HOTAIR functionally decreased OCSC phenotypes and malignant potential and reprogrammed HGSOC to a less stem-like phenotype. There is an urgent need to develop new therapeutic strategies to target OCSCs and overcome chemoresistant OC, and the results of this study suggest that targeting HOTAIR in combination with epigenetic therapies may represent a novel therapeutic strategy to prevent tumor relapse in OC. Citation Format: Weini Wang, Yanchi Zhou, Ji Wang, Ali Ozes, Heather M. O’Hagan, Anirban Mitra, Kenneth P. Nephew. HOTAIR functionality and regulation in ovarian cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2440.
Abstract 1528: 6B5, an anti-human B7-H3 therapeutic antibody that enhances antibody-dependent cellular cytotoxicity and inhibits tumor growth in B7-H3-humanized mice
Authors: Yunyun Chen, Jiangmei Li, Yanan Guo, Wenqi Hu, Ting Mao, Li Hui, W. Frank An, Yi Yang, Feng Li
Journal: Cancer Research (2023)

Abstract B7-H3 (CD276) is a type I transmembrane protein belonging to the B7 family of immune-regulatory ligands. Initially reported as a costimulatory signal of human T cells, increasing evidence suggests that it may also have coinhibitory function. TLT-2 has been identified as a potential cognate receptor for B7-H3, but others may exist. Overexpression of B7-H3 protein is found in a variety of human cancers, including lung adenocarcinomas, neuroblastomas, gliomas, and pancreatic tumors—and is associated with poor prognosis and survival. While B7-H3 can promote T cell activation and anti-tumor responses in the context of CD3 stimulation, its coinhibitory function inhibits T and NK cell activity in the tumor microenvironment. We generated 6B5, a fully human B7-H3 monoclonal antibody, from murine B7-H3 knock-out RenMab™ mice, which contain the full human immunoglobulin variable domain. 6B5 is cross-reactive with rodent and cynomolgus monkey B7-H3. It displays higher affinity for tumor cell lines than Enoblituzumab. 6B5 has no staining on normal human tissues. In vitro antibody-dependent cellular cytotoxicity (ADCC) against H520 squamous cell carcinoma cells was potentiated by 6B5 relative to Enoblituzumab and, critically, did not exhibit the hook effect at high dosage. In vivo efficacy of 6B5 in humanized B7-H3 mice bearing murine EL4 lymphomas was comparable to Enoblituzumab. ADCC enhancement in vivo was comparable to afucosylation or five-point mutations. Epitope mapping revealed non-overlapping B7-H3 binding epitopes of 6B5 and Enoblituzumab. Taken together, these data suggest that 6B5 is a promising therapeutic anti-human B7-H3 IgG monoclonal antibody that may find clinical application in a range of cancers, including current refractory types. Citation Format: Yunyun Chen, Jiangmei Li, Yanan Guo, Wenqi Hu, Ting Mao, Li Hui, W. Frank An, Yi Yang, Feng Li. 6B5, an anti-human B7-H3 therapeutic antibody that enhances antibody-dependent cellular cytotoxicity and inhibits tumor growth in B7-H3-humanized mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1528.
Abstract 3213: Association of Tumor Treating Fields (TTFields) with survival in newly diagnosed glioblastoma: A systematic review and meta-analysis
Authors: Patrick Conlon, Gitit Lavy-Shahaf, Noa Urman, Matthew T. Ballo
Journal: Cancer Research (2023)

Abstract Background: Tumor Treating Fields (TTFields) became an FDA-approved treatment option for patients with newly diagnosed GBM in 2015 on the basis of the randomized controlled EF-14 trial. Subsequent approvals worldwide and increased adoption of TTFields has led to the question of whether or not a consistent survival benefit has been observed in the real world setting, and whether device usage has played a role. Methods: We conducted a literature search using PubMed, Embase, and Google Scholar to identify clinical studies evaluating overall survival in adult patients with GBM treated with TTFields. Comparative studies and single-cohort studies reporting on survival outcomes were included in the analysis. Inter-study heterogeneity was assessed using the Cochran Q test and quantified using the Higgins I2 statistic. Results: Of 7 studies evaluating the clinical efficacy of TTFields in newly diagnosed patients, 5 studies (reporting on a total of 1,228 patients) compared the addition of TTFields to standard of care (SoC) vs SoC alone, and were included in a pooled analysis for overall survival. Meta-analysis of comparative studies indicated a significant improvement in overall survival for patients treated with TTFields vs those not receiving treatment. Inter-study heterogeneity was examined, and a sensitivity analysis indicated the pooled effect was robust and not dependent on any individual study. Furthermore, among studies reporting data on TTFields device usage, an average device usage rate of 75% or higher was found to consistently associate with prolonged survival when compared to an average usage rate below 75% (P = 0.001). Conclusions: Pooled analysis of comparative TTFields studies suggests survival may be improved with the addition of TTFields to standard chemoradiotherapy treatment for patients with newly diagnosed GBM, and that a 75% usage rate may be meaningful in the real-world setting. Citation Format: Patrick Conlon, Gitit Lavy-Shahaf, Noa Urman, Matthew T. Ballo. Association of Tumor Treating Fields (TTFields) with survival in newly diagnosed glioblastoma: A systematic review and meta-analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3213.
Abstract 275: Harnessing chemerin signaling as a novel therapeutic vulnerability in ccRCC
Authors: Dazhi Wang, Scott Welford, James Brugarolas, Sze K. Tan
Journal: Cancer Research (2023)

Abstract Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive subtype of kidney cancer, accounting for 70-80% of the cases. While surgical resection of early-stage tumors remains the standard care for patients, advanced ccRCC, metastatic or recurrent, portends a 5-year survival rate of only 12%, primarily due to insensitivity toward conventional chemotherapy. ccRCC is identifiable histologically by its dramatic lipid storage phenotype, similar to adipocytes; yet the role of lipid metabolism in ccRCC is poorly understood. One of the well-established risk factors for ccRCC is obesity and given that adipose tissue is known to produce a variety of pro-adipogenic signaling molecules (called adipokines), we hypothesized that adipokine signaling might be involved in the etiology of ccRCC. We recently identified a pro-tumorigenic adipokine protein, chemerin (RARRES2), that is positively correlated with tumor aggressiveness. Suppression of chemerin via either monoclonal antibody or siRNA led to reduction in lipid storage and significant tumor growth impairment in both in vitro and in vivo models by inducing ferroptosis. We next investigated the signaling mechanisms of chemerin and have found that chemerin drives downstream cellular activities and lipid deposition through either of the two receptors, GPR1 and CMKRL1. We further demonstrated that chemerin signals to both receptors to drive the expression adipose triglyceride lipase (ATGL) that frees up fatty acid from lipid depositions. In addition, Chemerin/CMKLR1 signaling axis further drives the activation of SREBP-mediated lipogenesis pathway. By using a small molecule antagonist specific for CMKRL1, α-NETA, we could suppress ccRCC tumor growth by inhibiting intracellular lipid droplet formation both in vitro and in vivo through the activation of ATGL-mediated lipolysis pathway and suppression of SREBP-mediated lipogenesis pathway. We have therefore shown the possibility of targeting Chemerin/CMKLR1 axis both genetically and pharmacologically to suppress the growth of ccRCC by increasing ferroptosis. Overall, our studies have identified chemerin/CMKLR1 axis as a promising therapeutic target that weakens ccRCC by modulating its lipid metabolic profiles and validated such vulnerability by using a more clinically relevant PDX orthotopic model. Further mechanistic investigations revealed overlapping yet distinct pathways downstream of chemerin that could potentially yield combinational strategies to treat ccRCC patients. Citation Format: Dazhi Wang, Scott Welford, James Brugarolas, Sze K. Tan. Harnessing chemerin signaling as a novel therapeutic vulnerability in ccRCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 275.
Abstract 1253: Dietary tryptophan catabolite released by intratumoral<i>Lactobacillus reuteri</i>facilitates aPD-L1 therapy
Authors: Mackenzie Bender, Alex McPherson, Catherine Phelps, Diwakar Davar, Dario A. Vignali, Hassane Zarour, Marlies Meisel
Journal: Cancer Research (2023)

Abstract The use of probiotics by cancer patients is increasing, including amongst those undergoing immune checkpoint inhibitor (ICI) therapy. Here, we elucidate a critical microbial-host crosstalk between probiotic-released aryl hydrocarbon receptor (AhR) agonist indole-3-aldehyde (I3A) and CD8 T cells within the tumor microenvironment that potently enhances spontaneous antitumor immunity and facilitates ICI therapy in preclinical melanoma. Our study reveals that probiotic Lactobacillus reuteri (L.reuteri) translocates to, colonizes, and persists within melanoma, where via its released dietary tryptophan catabolite I3A, it locally promotes interferon-γ-producing CD8 T cells, thereby facilitating ICI therapy efficacy. Moreover, L.reuteri secreted I3A was both necessary and sufficient for antitumor immunity, and loss of AhR signaling within CD8 T cells abrogated L.reuteri’s ability to restrain melanoma growth. Further, a tryptophan-enriched diet potentiated both L.reuteri- and ICI-induced antitumor immunity. Finally, we provide evidence for a potential role of I3A in promoting ICI therapy efficacy and survival in advanced melanoma patients. Citation Format: Mackenzie Bender, Alex McPherson, Catherine Phelps, Diwakar Davar, Dario A. Vignali, Hassane Zarour, Marlies Meisel. Dietary tryptophan catabolite released by intratumoralLactobacillus reuterifacilitates aPD-L1 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1253.
Abstract 6781: Spatial omics using spatially-resolved laser-activated cell sorting for cancer biomarker discovery
Authors: Amos C. Lee, Sumin Lee, Sunghoon Kwon
Journal: Cancer Research (2023)

Abstract Cancer is spatially heterogeneous in terms of genetic molecules. Revealing genomic, epigenomic, transcriptomic, and epitranscriptomic features that are unique to the malignant cell populations within cancer lead to cancer biomarker discoveries that can be translated into diagnostic or therapeutic tools. Here, we introduce spatially-resolved laser-activated cell sorting (SLACS) technology coupled to next generation sequencing and mass spectrometry that analyzes genetic molecules from regions of interest within spatial context. Specifically, we demonstrate application of SLACS in various cancers such as breast cancer, glioblastoma, glioma, meningioma, multiple myeloma, and leukemia. Examples of discovering cancer biomarker and their mechanism of action within spatial context are also provided. Specifically, we describe Select-seq which isolates the regions of interest as small as single cells from the immunofluorescence stained tissue and obtains the full-length transcriptome data. We demonstrated Select-seq on tumor tissue section from triple negative breast cancer patient who have received neoadjuvant chemotherapy. Select-seq produced full-length spatial transcriptome data, with which we analyzed the transcriptomic and epitranscriptomic features including alternative splicing variant, complementarity-determining region analysis of B cells, and even adenosine-to-inosine base editing. We were also able to analyze the immune- and stem-cell-like microniches, in which the complex mechanisms behind ferroptosis inhibition might suggest therapeutic options for the TNBC patients. Bridging spatial technologies to omics technologies, the discovery of specific markers within spatial context will provide insights into the next generation diagnostics and cancer therapeutics such as cancer vaccines. Citation Format: Amos C. Lee, Sumin Lee, Sunghoon Kwon. Spatial omics using spatially-resolved laser-activated cell sorting for cancer biomarker discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6781.
Abstract 3103: Dual targeting MYC G-quadruplex and topoisomerase I by indenoisoquinolines for cancer therapy
Authors: Danzhou Yang, Mark Cushman, Kai-Bo Wang, Mohamed S. Elsayed, Guanhui Wu, Adam J. Buric, Mercedes DeMoss
Journal: Cancer Research (2023)

Abstract MYC is one of the most important oncogenes and is overexpressed in a number of human cancers. The G-quadruplex formed in the MYC oncogene promoter (MycG4) is a transcriptional silencer and amenable to small molecule targeting. G-quadruplexes are noncanonical four-stranded DNA or RNA secondary structures that have emerged as novel therapeutic targets. Indenoisoquinolines are human topoisomerase I inhibitors with improved physicochemical and biological properties as compared to the clinically used camptothecin anticancer drugs. Three indenoisoquinolines, indotecan (LMP400), indimitecan (LMP776), and LMP744, have entered phase I clinical trials in adults with relapsed solid tumors and lymphomas. However, some indenoisoquinolines showed potent anticancer activity without being strong topoisomerase I inhibitors, suggesting additional mechanisms of action. Herein, we demonstrate that a large number of anticancer indenoisoquinolines strongly bind and stabilize MycG4 in vitro, using fluorescence, nuclear magnetic resonance (NMR), and circular dichroism (CD) spectroscopy, as well as gel electromobility shift assay (EMSA). In addition, MycG4-interactive indenoisoquinolines lower MYC mRNA and protein levels in vivo, as shown by western blot and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) experiments. Structure-activity-relationships of MycG4 recognition by indenoisoquinolines were investigated to understand structural requirements for binding. Systemic analysis of indenoisoquinoline derivatives led to the discovery of a synergistic effect of MYC inhibition and topoisomerase I inhibition on anticancer activity. Therefore, these results indicate that targeting the MYC promoter G-quadruplex to downregulate MYC is a new mechanism of action for anticancer indenoisoquinolines. Moreover, our data reveals dual targeting of MycG4 and topoisomerase I as a novel strategy for cancer therapy. Citation Format: Danzhou Yang, Mark Cushman, Kai-Bo Wang, Mohamed S. Elsayed, Guanhui Wu, Adam J. Buric, Mercedes DeMoss. Dual targeting MYC G-quadruplex and topoisomerase I by indenoisoquinolines for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3103.
Abstract SY23-02: Mechanistic insights of brain tumor relapse
Authors: Jezabel Rodriguez-Blanco
Journal: Cancer Research (2023)

Abstract Pediatric brain tumors are the number one cause of cancer-related death in children, with medulloblastoma (MB) being the most common type. Genomic-based classification has enabled the stratification of MB into four distinct molecular subgroups: WNT, Sonic Hedgehog, Group 3, and Group 4. Such classification allows a better understanding of these malignancies, which has resulted in a significant improvement in the stratification of clinical trials. Despite substantial progress made in the field, still, 30% of children with MB will relapse. Recurrent disease in MB is commonly metastatic and virtually none of these patients will live beyond the 1-year hallmark. These sobering statistics underscore the largely unmet need for brain tumor therapies aimed at treating or preventing the emergence of relapsed disease. In this session, we will review recent advances in the identification of treatment-resistant pools of brain tumor cells, giving special emphasis to the signaling mechanisms that allow these cell populations to evade therapeutics and expand. Citation Format: Jezabel Rodriguez-Blanco. Mechanistic insights of brain tumor relapse. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr SY23-02.